Download New Directions in Systemic Therapy of Pancreatic Cancer

The low survival rate for patients
with pancreatic cancer emphasizes
the need for better systemic therapy
for those who are inoperable as
well as effective adjuvant therapy
for those who undergo resection.
Jar. 1994. Cavan B. Gonzales, San Ildefonso. Courtesy of the Heard Museum, Phoenix,Arizona.
New Directions in Systemic Therapy of
Pancreatic Cancer
Alexander S. Rosemurgy, MD, and Francesco M. Serafini, MD
Background: The aggressiveness of pancreatic adenocarcinoma makes it a deadly disease, with its incidence
rate and fatality rate almost equal. Surgery represents the only means to provide cure to patients with
pancreatic cancer, though the 5-year survival is less than 10%.
Methods: We review the data on surgical and systemic therapies and provide more details on a newer
biologically based medical approach.
Results: Neoadjuvant chemotherapy protocols are confined to one or two institutions, and adjuvant
chemotherapy and chemoradiation therapy protocols are far from being standardized. Chemoradiation
therapy for locally advanced pancreatic cancer offers limited benefits. Protocols that include gemcitabine and
5-fluorouracil, while comparing favorably to historical controls, offer median survivals at approximately
8 months.
Conclusions: More effective protocols with combinations of approaches agents are needed to improve the
treatment of pancreatic cancer.
Introduction
Pancreatic cancer is an aggressive cancer. The
incidence of pancreatic cancer is increasing, but little
progress has been made in long-term survival. It
From the Center for Digestive Disorders at the University of South
Florida, Tampa, Florida.
Address reprint requests to Alexander S. Rosemurgy, MD, Tampa
General Hospital, PO Box 1289, Suite F-145, Tampa, FL 33601.
No significant relationship exists between the authors and the
companies/organizations whose products or services may be
referenced in this article.
September/October 2000, Vol. 7, No.5
remains one of the few cancers whose death rate nearly equals its incidence. As we enter the new century,
the 2-year survival rate associated with pancreatic cancer remains approximately 10%.1
There are many reasons why survival with pancreatic cancer is poor: (1) The symptoms and signs of
pancreatic cancer are so nonspecific that patients
often present with the disease in an advanced stage.
Patients who present with jaundice generally have a
better prognosis than patients who do not have jaundice because this condition causes patients to seek
care when their cancers are at an earlier stage. (2)
Cancer Control 437
Because symptoms and signs are nonspecific, physicians may not make the diagnosis of pancreatic cancer
and thus may allow the tumors to further advance. (3)
Increasingly, bureaucratic delays in our health care system prolong time from diagnosis to definitive care,
potentially impacting survival. Patient delay, physician
delay, and system delay result in patients presenting
with advanced disease and promote the need for
improved therapy for patients with advanced stage
pancreatic cancer.
Though many modalities are available to diagnose
or stage pancreatic cancer, computed tomography (CT)
scan remains the relative gold standard. Unresectability by CT scanning is accurate to 95%, but resectability
by CT scan is accurate to only 70%.2 Patients thought
to have unresectable tumors will generally undergo further testing to document unresectability of their cancers. These additional tests may include angiography
with venous phase study or CT portography. Recently,
the role of magnetic resonance imaging (MRI)-cholangiography has been emphasized in the diagnosis and
preoperative staging of pancreatic cancer. We have not
been so impressed with MRI studies because fine
details generally are not apparent. Laparoscopy, even
though adding expenses to the cost of care, has an
increasing role in intraoperative staging of pancreatic
cancers, mainly by detecting small peritoneal implants
and small superficial liver metastasis.
Percutaneous fine-needle aspiration or biopsies of
pancreatic cancers should be undertaken only in selected patients because of risks of dissemination. Also, sampling error will occur and will serve to understage cancers or will fail to document existing cancers.3 Fineneedle aspiration and percutaneous biopsy have a role
only in patients with unresectable disease when the
intent is to document the unresectable nature of the
pancreatic cancer.3 For example, a liver biopsy establishes not only the cancer, but also its advanced stage
and unresectable state. Patients with pancreatic masses that appear resectable at CT should not undergo percutaneous biopsy or fine-needle aspiration. Such procedures violate the tumors and, whatever the outcome,
will not change the therapeutic plan, though they may
disseminate cancer cells.
The specific cause of pancreatic cancer remains
unknown. Rather, it seems most likely that there are
many causes of pancreatic cancer. The genetic alterations in patients with pancreatic cancer are notable
and are increasingly well described. Marked abnormal
karyotypes are found in 40% of patients with pancreatic cancer. Fractional arm loss on chromosomes correlates with prognosis and may involve chromosomes 1,
6, 7, 9, 12, 13, 17, 18, and 20. Alterations in a host of
438 Cancer Control
genetic markers such as k-ras, raf, DCC, and p53 have
been well described.4,5 Mutations at these sites impart
a poorer prognosis.
Resection offers the only hope of cure in treating
pancreatic cancer. That concept is often lost in the
therapeutic plan. Resection should be aggressively
sought and pursued. Unfortunately, operability is relatively low and resectability is lower yet. This results in
only a minority of patients with pancreatic cancer
undergoing resection with curative intent. Resection
without curative intent offers improved survival when
compared to unresectable tumors. Operative mortality
over the years has decreased, but survival with resection remains less than 20% at 5 years in most studies.
These numbers not only underscore the need for systemic therapy for patients who are inoperable, but also
emphasize the need for improved adjuvant therapy for
patients who undergo surgery for cure.
Postoperative staging can be helpful in estimating
survival. Several factors have been found to correlate
with survival: tumor size, nodal status, distant metastasis, genetic markers (eg, p53, k-ras, etc), lymphatic invasion, perineural invasion, and surgical margins. Of
these many factors that are important in postoperative
staging, surgeons have control over only the surgical
margins. Clean surgical margins should be aggressively
sought; however, the size of the tumor, presence of
lymph node metastases, and perineural invasion may
preclude long-term survival even with clean surgical
margins. This illustrates the futility of aggressively seeking clean surgical margins in patients with advanced
primary tumors.
Neoadjuvant Therapy in
Pancreatic Cancer
Neoadjuvant therapy has been advocated by some
to improve curative resection rates and survival. Proponents hypothesize that neoadjuvant therapy decreases the chance of leaving microscopic and gross residual
disease at the time of resection and thus decreases the
chance of intraoperative peritoneal tumor spread.
Neoadjuvant regimens would allow delivery of radiation to well-oxygenated cancer cells and would avoid
delays of chemotherapy due to complications after
resection. On the other hand, neoadjuvant therapy can
delay surgical treatment of pancreatic cancer, and it
carries its own morbidity.
Neoadjuvant therapy trials have been reported by
many, including investigators at the University of TexasM.D. Anderson Cancer Center6 and Fox Chase Cancer
Center.7 Most studies involved limited numbers of
September/October 2000, Vol. 7, No.5
patients, and most reported on combinations of 5-fluorouracil (5-FU) or cisplatin with external-beam radiation
therapy (EBRT).8,9 Patients undergoing neoadjuvant
chemoradiation therapy at M.D. Anderson Cancer
Center experienced a lower rate of local recurrences,
but 25% of those studied were unable to receive postoperative adjuvant treatment because of prolonged
recovery after resection. Unfortunately, regimens have
varied from study to study, and many trials involved
historical controls. Due to the variability among the
studies, the study designs and sizes, and the therapies
chosen, neoadjuvant chemotherapy has not been conclusively shown to improve survival for patients undergoing resection for pancreatic cancer
Adjuvant Therapy in Pancreatic Cancer
There are no established guidelines for adjuvant
therapy following pancreatectomy. Several chemotherapy trials have been undertaken over the years. Many
of these trials have included radiation therapy. These
trials have produced varied results with varied regimens, often involving historical controls. Because of
the limited scientific design of these studies and the
lack of particularly efficacious therapy, the role of
chemotherapy and radiation therapy remains generally
unestablished.
Patterns of failure after pancreatectomy are notable,
for they tell where the adjuvant therapy should be
directed. Following pancreatectomy, recurrent disease
generally appears within the nodal basin first. Approximately 80% of all failures will occur locoregionally. Sites
of locoregional recurrence generally are the lymphatic
tissues and nodes along the superior mesenteric vein,
the portal vein, and the superior mesenteric artery.
Given sufficient time, recurrent disease will appear
in many different organs and locations. Distant failure
following pancreatic resection usually occurs in the
liver and by spread through the peritoneal cavity.
Hepatic metastasis may be seen in as many as 60% of
patients in large series, and peritoneal metastasis may
occur in as many as 40% of patients following pancreatectomy. The appearance of cancer in distant organs
and at multiple sites generally follows locoregional
recurrence and presages rapid deterioration and death.
Several chemoradiation studies in patients with
resectable pancreatic cancer have been undertaken.
However,these studies generally were not well designed,
either involving small numbers of patients or undertaking comparisons with historical controls. Consequently,
these trials failed to establish therapy guidelines in the
treatment of pancreatic exocrine adenocarcinomas. The
September/October 2000, Vol. 7, No.5
two most widely noted studies of adjuvant treatment of
pancreatic cancer are the Gastrointestinal Tumor Study
Group (GITSTG) trials10,11 published in 1985 and 1987.
The 1985 trial was a prospective, randomized study of
patients with pancreatic cancers undergoing pancreatectomy. This trial randomly assigned therapies between a
control arm (only resection, 22 patients) and a treatment
arm (resection followed by 5-FU and EBRT, 21 patients).
The trial showed a survival benefit between the treated
group (median survival = 21 months) and the control
group (median survival = 11 months) (P=0.3). Subsequently, the second trial of the GITSTG reported a median survival of 18 months in 30 patients undergoing EBRT
and 5-FU therapy after pancreatic resection. The small
number of patients enrolled from multiple centers over
an extended period of time, the absence of a control arm
in the second paper, and the inclusion of patients with
cancers of the pancreatic head,body,and tail raised questions about the reliability of the data. Though these trials have been widely quoted, their shortcomings are
major liabilities. Conclusions from these studies should
not be accepted without considerable reservations.
Preliminary results of a phase III trial from
Europe,12 reported in abstract form, that compared
EBRT plus 5-FU with follow-up chemotherapy (folinic
acid followed by 5-FU) to no adjuvant treatment failed
to demonstrate survival advantages in treated patients
following pancreatic resection. Median survival was
23.5 months for patients receiving adjuvant therapy
compared with 19 months for patients undergoing
surgery only. This is the largest trial of adjuvant therapy for pancreatic cancer and has accrued more than
400 patients to date.
Few studies have investigated the role of
chemotherapy as sole adjuvant treatment after pancreatic resection. A randomized study from Europe,13 published in 1993, accrued nearly 60 patients over a 4-year
period. Patients were randomized to either a control
group (pancreaticoduodenectomy only) or a treatment
group (surgery plus polychemotherapy). The polychemotherapy regimen included 5-FU, doxorubicin,
and mitomycin C. This trial documented a substantial
advantage in median survival in the treated group (23
months vs 11 months), but treated patients experienced considerable toxicity that often required hospitalization. In addition, adjuvant polychemotherapy
proved not to be beneficial at longer follow-up (the 5year survival rate in the treated group was 8% vs 4% in
the control group). The number of patients entered
over a significant time span raises concerns about any
differences in survival that might be suggested.
Intraoperative postresection radiotherapy (IORT)
has been applied as adjuvant treatment of pancreatic
Cancer Control 439
cancer. No controlled, randomized study has compared
survival and outcomes among patients undergoing
IORT, EBRT, or control therapy. Apparently, IORT results
in fewer local recurrences but higher perioperative
complication rates.14 No role for IORT has been established, though IORT has been widely applied, mostly in
the 1980s.
Adjuvant intra-arterial regional chemotherapy has
been studied in a few trials involving small numbers of
patients. Link et al15 reported adjuvant intra-arterial
polychemotherapy on 20 patients and documented
median survivals of 21 months. The rationale behind
this treatment is to deliver high doses of drug to the
resected tumor bed. Potential drawbacks are arterial
complications (eg, thrombosis), dislodgment of the
catheter, mucosal damage from the injection of the
chemotherapeutic agent, and dispersion of the drug
due to the rich vascular arterial network of the celiac
trunk and the superior mesenteric artery.
No studies document definitive efficacy of adjuvant therapy. The two studies from the GITSTG and,
more recently, the larger European trial referred to
above have demonstrated some advantage of adjuvant
treatment for patients with pancreatic cancer. Generally, trials of adjuvant treatment of pancreatic adenocarcinoma included small numbers of patients or were
poorly controlled. Though there are reports purporting
efficacy of adjuvant therapy, the scientific validity of the
reports is generally lacking. Therefore, the applicability
and implications of the results of these trials need to be
cautiously interpreted. Unfortunately, there remains no
well-accepted, effective “gold standard” for treating
patients in an adjuvant setting with pancreatic cancer.
bination of 5-FU and EBRT, though there is not a strong
database to support this approach. Though studies are
available to support this standard, studies of significant
numbers and sound design are lacking.
More recently, gemcitabine, a deoxycytidine analogue capable of inhibiting DNA replication and repair,
has been used in the treatment of advanced pancreatic
carcinoma. Gemcitabine was compared to 5-FU in a
prospective, randomized trial using “clinical benefit
response” as a marker of efficacy.17 Clinical benefit
response was measured by analgesic consumption, pain
intensity, performance status, weight change and, as a
secondary end-point, survival. In this trial, emphasis
was placed on quality of life rather than on survival.
Randomization involved 126 patients, with 63 patients
receiving either gemcitabine or 5-FU. The patients
receiving either therapy were of similar age, and a similar number had stage IV disease. Clinical benefit
response favored patients receiving gemcitabine,
though the number of patients involved was small. Of
patients receiving gemcitabine, 14 (22%) experienced a
clinical benefit response, whereas of patients receiving
5-FU, only 3 (5%) experienced a clinical benefit
response. Though these numbers seem different, it is
noted that the number of patients in the study is small.
Survival with gemcitabine was longer on average than
with 5-FU (5.7 months and 4.2 months, respectively).
The probability of surviving 1 year for those receiving
gemcitabine was 18% compared with 2% for those
receiving 5-FU. These survival numbers are neither significantly different nor impressive. They point out the
aggressive nature of pancreatic cancer and the resistance of these cancers to systemic chemotherapy.
Therapy for Locally Advanced
Pancreatic Cancer
Since many studies utilized historical controls when
evaluating therapy for pancreatic cancer, conclusions
from such studies can be accepted only with trepidation
and uncertainty. Nonetheless, when considering new
therapies for patients with unresectable pancreatic cancer, it is important to remember that survival with 5-FU is
only 2% at 1 year and mean survival is 4.2 months. Similarly, it is important to remember that gemcitabine alone
is associated with an 18% probability of 1-year survival
and a mean survival of 5.7 months. These poor survival
statistics have led us to seek other avenues of therapy.
For patients with unresectable pancreatic cancer or
with residual cancer after resection, there are no established guidelines for therapy. Most frequently, drugs
such as 5-FU, mitomycin C, and cisplatin are combined
with some form of radiation therapy. Polychemotherapy has not shown any advantage over single-chemotherapy regimens. Better results with radiation therapy
seem to occur with combined chemotherapy and radiation therapy.16 Many patients currently receive a com-
Several phase I and II trials, which included combinations of EBRT, 5-FU, and gemcitabine, coupled with
other drugs such as epirubicin or cisplatin, have been
reported recently. Most of these reports demonstrated
that the combination of 5-FU and gemcitabine is safe
and well tolerated in most patients with advanced pancreatic cancer. These results, though better than those
with historical controls, are not promising, with median survival at best around 10 months.18-20
Given the inefficacy of adjuvant therapy, we
believe that surgeons who aggressively resect pancreatic cancers have an obligation to seek new and innovative ways to promote not only survival in patients following resection, but also survival and quality of life in
patients who have unresectable disease.
440 Cancer Control
September/October 2000, Vol. 7, No.5
The survival of patients presenting with local recurrence after “curative” pancreatic resection for malignancy is dismal at best. Standardized therapeutic options
are lacking. Surgery with resection of recurrent tumor
masses represents a formidable undertaking, is generally not possible, and is not considered conventional, but
sometimes it can offer advantages in survival.21 Operations to resect locoregional recurrences are generally
not possible and should not be routinely considered.
Effective chemotherapy and radiation therapy protocols for inoperable recurrent disease are lacking.
Recently, intra-arterial polychemotherapy has been proposed to palliate recurrent disease after pancreatic
resection. Initial results appeared to be satisfactory, particularly in terms of pain relief, but long-term survival
remains poor.22
Metalloproteinase Inhibition in the
Treatment of Pancreatic Cancer
The breakdown of extracellular matrix and the disruption of cellular architecture are the hallmarks of
cancer. Metalloproteinases degrade all components of
extracellular matrix, including fibrillar and nonfibrillar
collagens and basement membrane glucoproteins. In
this way, metalloproteinases promote the breakdown of
extracellular matrix and the disruption of intercellular
architecture, allowing for aggressive contiguous growth
and systemic dissemination of cancers. In addition,
metalloproteinases promote angiogenesis.
Metalloproteinases are present in high levels in a
host of solid organ cancers. We and other investigators
have found matrix metalloproteinase (MMP) gene
expression to be increased in pancreatic cancers relative to normal pancreas. MMP gene expression is
increased for multiple forms of MMPs including MMP-2
and MMP-9. MMP-2 seems particularly important in the
growth and dissemination of pancreatic cancer.23,24
We studied 21 human pancreatic cancers for MMP
content and found that tumor levels of MMP-2 in the
active form strongly correlate with nodal status and
tumor stage. To a lesser extent,MMP-9 in the active form
correlates with nodal status and stage. Neither MMP-9
nor MMP-2 in the active and latent form correlates with
tumor size, implying that tumors with low MMP levels
can grow to a large size prior to dissemination.25
To study the role of metalloproteinase inhibition in
the growth and dissemination of human pancreatic
cancer, we used a nude mouse model of human pancreatic cancer. In this effort, cancers resected from
patients have been grown in cell culture. Cancer cells
September/October 2000, Vol. 7, No.5
were then operatively implanted into the head of the
pancreata of the mice. Survival studies were undertaken, and serial evaluations of tumor growth were conducted. Necropsies allowed us to study cancer implantation and tumor growth.
It seems clear that, in this model, metalloproteinase
inhibition by the metalloproteinase inhibitor Batimastat
(BB-94) impeded implantation, delayed tumor growth,
and prolonged survival. In study after study, mice
begun on Batimastat as long as 1 week following operative implantation of neoplastic cells had a lesser rate of
tumor implantation than mice receiving vehicle control. In general terms, implantation decreased by 15%
in mice receiving BB-94 even when therapy was started as long as 1 week following tumor cell implantation.
The specific cause of this is not known, though it seems
that the efficacy of the metalloproteinase inhibitor is
such that the immune status of the mouse is sufficient
to eliminate all traces of the injected cancer cells.25,26
Mice receiving the parenteral inhibitor Batimastat
have been shown in a host of ways to have smaller
tumors. Tumor weight and tumor volume were
reduced by the inhibitor and, consistent with this, CA
19-9 levels were dramatically reduced in mice that
were given Batimastat. Metalloproteinase inhibition
was also associated with less tumor invasion and fewer
metastases in this mouse model. Survival in mice that
were given Batimastat was significant and surpassed
survival in mice given the vehicle control, further promoting the efficacy of metalloproteinase inhibition.25
We found improvements in survival in study after study,
even when therapy is initiated at a time distance from
implantation. Survival particularly improved when
therapy was initiated prior to tumor implantation.26
Survival of mice starting Batimastat therapy prior to
tumor implantation was almost indefinite and was
indistinguishable from mice receiving sham injections
rather than injections of cancer cells.
Combining Cytotoxic Therapy With
Metalloproteinase Inhibition
Gemcitabine and metalloproteinase inhibitors
obviously have different mechanisms of action. The
possibility of having added efficacy with combination
therapy must be considered and the possibility of synergistic activity may be possible. However, given their
differences in action, different and varied complications may be possible with such therapy and as well,
and accentuated or exaggerated complications may
occur. To investigate the possibility of added efficacy
with combination therapy, we studied the combination
of gemcitabine and Batimastat in the nude mouse
Cancer Control 441
model of human pancreatic cancer utilizing a wellestablished, well-differentiated human pancreatic adenocarcinoma cell line (HPAC).27
As seen in our previous studies, cancer cell implantation in mice receiving vehicle control was not uniform. Approximately 10% of mice receiving vehicle
control beginning 1 week following cancer cell implantation did not harbor malignancy at necropsy. Similar
but slightly diminished rates of implantation were seen
in mice receiving Batimastat or gemcitabine. Mice
receiving Batimastat and gemcitabine had greatly
diminished rates of implantation, as the vast majority of
mice receiving such therapy did not experience successful implantation of cancer cells, even though therapy was started 1 week following operative orthotopic
implantation of cancer.27 While this impedes the study
of cancer growth in mice receiving this combination
therapy, it documents that combination therapy offers
new hope of controlling pancreatic cancer, particularly
in circumstances of minimal cancer. This suggests a
role for such combination therapy for patients in need
of adjuvant therapy.
Studying only mice that had cancer, after eliminating all mice that did not demonstrate implantation of
cancer at necropsy, survival was significantly promoted
by combination therapy of Batimastat and gemcitabine.27 With combination therapy, mice with cancer
experienced indefinite survival, which ended only with
sacrifice. Similar to our other studies, mice receiving
vehicle control had progressive decreases in survival
beginning at 40 days following implantation. This survival curve was relatively poorer, though not statistically different than survival curves associated with Batimastat or gemcitabine alone. Other previous studies of
ours have shown significant differences in survival
between mice receiving vehicle control or Batimastat,
but this specific trial to test combination therapy did
not. Similar to these differences in survival, assessment
of tumor MMP levels shows that mice receiving gemcitabine in combination with Batimastat had lower levels
of active and latent MMP-2 and MMP-9 compared with
vehicle control. Lowest levels of active and latent MMP2 and MMP-9 were seen with combination therapy relative to other forms of therapy and particularly relative
to vehicle control. Similarly, serum MMP levels were
lowest in mice receiving combination therapy.27
Metalloproteinase Inhibition in
Patients With Pancreatic Cancer
There is a growing body of data documenting the
efficacy of metalloproteinase inhibition for patients
with cancer. Patients diagnosed with small-cell lung
442 Cancer Control
cancer, melanoma, ovarian cancer, and pancreatic cancer have been studied. A survival study28 involving
patients in the United States and the United Kingdom
with inoperable pancreatic cancer was undertaken in
the early 1990s. This trial was designed to mirror in
many ways the inclusion criteria utilized when 5-FU
was compared to gemcitabine in patients with inoperable pancreatic cancer. CA 19-9 levels were used as a
surrogate marker of efficacy in this trial, as the mechanism of MMP inhibition seems to be optimally studied
through such a surrogate marker. Patient criteria
included unresectable pancreatic cancer and an
increasing CA 19-9 of 25% or more in the month prior
to inclusion into the trial. Given this patient population, 74 patients were studied and only 3 patients were
later excluded. Median survival was 125 days upon
conclusion of the trial, with a number of patients still
alive. Survival to 365 days was estimated to be approximately 30%. With all the caveats of using historical
controls, this number seems superior to the 18% 1-year
survival commonly associated with gemcitabine.
Patients could be divided into two groups based on
the rate of rise of CA 19-9 following initiation of therapy. Retrospectively, it was observed that patients who
continued to have a rise in their CA 19-9 of more than
25% in the month following initiation of therapy had a
poorer outcome, with a projected survival of approximately 22% at 1 year. Patients with a decrease in the
rate of rise in their CA 19-9 or had an actual decrease in
their CA 19-9 following initiation of therapy had a
much better survival rate, which approached 60% at
one year.28,29 This gives hope that patients early in the
course of their therapy could be evaluated for response
and therapy could be continued for patients with a
high probability of long-term survival.
Gemcitabine has been compared to an oral metalloproteinase inhibitor, Marimastat (BB-2156), in a
prospective, randomized clinical trial30 that was presented at the American Society of Clinical Oncology
meeting in 1999. This randomized trial compared Marimastat to gemcitabine as first-line therapy for patients
with unresectable pancreatic cancer. The randomized
comparison involved three dose levels of Marimastat vs
a standard regimen of intravenous gemcitabine. A total
of 414 patients were enrolled to receive either Marimastat (5 mg, 10 mg, or 25 mg b.i.d.) or gemcitabine
(1,000 mg/m2). The objective of this trial was to evaluate survival (as a primary end-point) and time to disease
progression (as a secondary end-point). Additionally,
quality of life, safety, and tolerability were secondary
end-points.
All patients entering into the trial had histological
or cytological diagnosis of unresectable pancreatic
September/October 2000, Vol. 7, No.5
cancer. All were more than 18 years of age, and all had
Karnofsky performance scores of more than 50%.
Patients with prior malignancies were excluded, and
all patients had adequate liver and renal function and
adequate bone marrow reserve. Patients entered into
the trial underwent minimization to ensure that all
groups were comparable in makeup. Minimization
criteria included tumor stage, Karnofsky score, recurrent vs newly diagnosed pancreatic cancer, sex, and
clinical center. Mean age, mean weight, gender distribution, Karnofsky performance score, stage of cancer,
and the presence of liver metastasis were equivalent
in all groups.
Primary mortality analysis documented that
patients receiving 5 mg or 10 mg of Marimastat b.i.d.
had similar survival curves. These curves were significantly inferior to patients receiving gemcitabine or the
25 mg b.i.d. dose of Marimastat. Survival with the 25
mg b.i.d. dose of Marimastat was similar to that
achieved with gemcitabine.
The median time for disease progression was 56,
59, and 57 days for Marimastat doses of 5 mg, 10 mg,
and 25 mg b.i.d., respectfully. Median time to disease
progression by gemcitabine was significantly longer
(115 days) (P<0.001). Patients with liver metastases
seemed to survive longer with gemcitabine, while
patients with extensive locoregional disease seemed to
survive longer with Marimastat therapy.
Studies of safety and tolerability documented few
adverse effects in patients receiving either gemcitabine
or Marimastat. Patients receiving any of the four therapies had similar numbers of adverse events. Most of the
adverse events were mild, and many of them were
more consistent with the underlying cancer than the
therapy being tested, such as vomiting, nausea, and constipation. Of significant complications, gemcitabine
was more often associated with hematologic complications such as leukopenia and thrombocytopenia. The
metalloproteinases inhibitors were more often associated with musculoskeletal complaints, the majority of
which were self-limiting. Musculoskeletal complaints
with metalloproteinase inhibition involved the hand
(particularly the dominant hand), followed by the
shoulder, then the lower extremeties. Most of the musculoskeletal complaints were minor, but they were the
primary reason for dose reduction and drug holiday for
patients receiving Marimastat.
This randomized study comparing Marimastat to
gemcitabine as a first-line therapy in patients with
unresectable pancreatic cancer documents no significant difference between the survival curves associated
with 25 mg b.i.d. of Marimastat or with gemcitabine.
September/October 2000, Vol. 7, No.5
In that regard, this study did not meet its end-point.
One-year survival associated with 25 mg b.i.d. of Marimastat was the same as that for patients receiving gemcitabine. The Cox proportional hazards model documented a dose-dependent effect of Marimastat, with
patients receiving 25 mg b.i.d. surviving longer than
patients receiving lesser doses. Although there were
differences in tolerability, gemcitabine and Marimastat
were generally well tolerated with no marked differences in safety. Expected hematologic complications
(gemcitabine) and musculoskeletal complications
(Marimastat) were seen. Complications associated
with rapid disease progression were noted, but they
did not affect the trial outcomes.
A multicenter study comparing gemcitabine with
gemcitabine plus Marimastat is currently in progress at
our institute. Data from this trial should be available in
the near future.
Conclusions
No effective therapy guidelines have been established for patients with pancreatic cancer, whether
measurable or microscopic disease. Though neoadjuvant and adjuvant therapy have support, studies undertaken to document efficacy have too often been
flawed in design and have involved therapies that are
generally inefficacious. Therapy for measurable residual or unresectable pancreatic cancer is attractive in
concept, though scientifically proven effective regimens have yet to be established to provide for extended survival. More effective therapies are being sought.
Until the results of studies of these approaches are
available, patients with pancreatic cancer would best
be served by participation in clinical studies that
involve that offer real hope of progress rather than
new ways to use 5-FU.
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